Intermediates and process for the production of optically active quinolonecarboxylic acid derivatives

ABSTRACT

Provision of a commercially advantageous method for producing an intermediate which is important for producing the antibacterial and which has a mother nucleus common to the antibacterial, and intermediates produced by such method. 
     A method for producing a compound represented by formula (VI): 
                         
which comprises the steps of treating a compound represented by formula (IV):
 
                         
with a base in the presence of a base to produce a compound represented by formula (V):
 
                         
and hydrolyzing this compound;
 
a compound represented by formula (II):
 
                         
a compound represented by formula (Ia):
 
                         
a compound represented by formula (V):
 
                         
and a compound represented by formula (VI).

TECHNICAL FIELD

This invention relates to a method for producing a 6-Hquinolonecarboxylic acid derivative (“6-H” means that the compound issubstituted with hydrogen at 6-position) which is an intermediate insynthesizing quinolonecarboxylic acid antibacterials, as well as tonovel intermediates in producing such quinolonecarboxylic acidderivative. The quinolonecarboxylic acid antibacterials are highlypromising as medicaments, agricultural chemicals and veterinary drugs.

BACKGROUND ART

Quinolonecarboxylic acid derivatives are widely used in medicine assynthetic antibacterials. However, emergence of resistant bacteriarepresented by MRSA has become a major obstacle in such treatments. Aquinolonecarboxylic acid derivative represented by the following formula(A):

is a compound capable of overcoming the problems associated with variousresistant bacteria since this not only exhibits excellent effects onMRSA but also has an antibacterial activity against resistantGram-positive bacteria. A known process for producing an intermediatehaving the mother nucleus of quinolonecarboxylic acid is shown by thefollowing reaction scheme (see, for example, Patent Document 1).

Patent Document 1: WO 02/040478 gazette

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The production methods currently known in the art, however, require alarge number of steps, and further, these include the step of using anorganolithium reagent at an extremely low temperature (−50° C.), andsuch step places a serious burden on the production process and hamperscommercial use of such method on a large scale.

Accordingly, the objects of the present invention are to provide acommercially advantageous method for producing an intermediate which isimportant in producing an antibacterial and which has a mother nucleuscommon to the antibacterial, as well as to provide intermediatesproduced by such method.

Means to Solve the Problems

The present inventors have made an extensive investigation, and havefound that a7-fluoro-1-[(1R,2S)-2-fluorocyclopropylamine]-1,4-dihydro-8-alkoxy-4-oxoquinoline-3-carboxylicacid can be produced in a commercially advantageous manner in 5 steps,for example, as shown by the reaction scheme described below, byconverting a 2,4-difluoro-3-alkoxybenzoic acid into an acid chloride ora mixed acid anhydride, condensing it with an ethylN,N-dialkylaminoacrylate to produce a3-dialkylamino-2-(2,4-difluoro-3-alkoxybenzoyl)acrylic acid derivative,and using the derivative as a key intermediate in producing the7-fluoro-1-[(1R,2S)-2-fluorocyclopropylamine]-1,4-dihydro-8-alkoxy-4-oxoquinoline-3-carboxylicacid to complete the present invention.

In this reaction scheme, X represents a halogen atom or an acyloxygroup, R¹ represents a lower alkyl group, R² and R³ represent the sameor different lower alkyl groups, and A represents nitrile group or analkoxycarbonyl group.

Accordingly, this invention provides a method for producing a compoundrepresented by the following formula (VI):

wherein R¹ represents a lower alkyl group which comprises the steps oftreating a compound represented by formula (IV):

wherein R¹ is as defined above and A represents nitrile group or analkoxycarbonyl group with a base to produce a compound represented byformula (V):

wherein R¹ is as defined above, and hydrolyzing this compound.

The compound represented by formula (IV) can be produced by reacting acompound represented by formula (II):

wherein R² and R³ represent the same or different lower alkyl groups,and R¹ and A are as defined above with (1R,2S)-2-fluorocyclopropylamine.

The compound represented by formula (II) can be produced by reacting acompound represented by formula (I):

wherein X represents a halogen atom or an acyloxy group and R¹ is asdefined above with a compound represented by formula (III)

wherein A, R², and R³ are as defined above.

The compound represented by formula (I) can be produced by reacting acompound represented by the following formula:

wherein R¹ is as defined above with a halogenating agent or an acidanhydride.

This invention also provides a compound represented by formula (II):

wherein R¹ represents a lower alkyl group, A represents nitrile group oran alkoxycarbonyl group, and R² and R³ represent the same or differentlower alkyl groups. This compound is an intermediate useful forsynthesizing the compound represented by formula (VI) which is anintermediate in producing 6-H quinolonecarboxylic acid derivativeshaving a strong antibacterial activity and which has a mother nucleuscommon to the 6-H quinolonecarboxylic acid derivatives.

This invention also provides a compound represented by formula (Ia):

wherein R¹ represents a lower alkyl group and X represents an acyloxygroup. This compound is an intermediate useful for synthesizing thecompound represented by the formula (VI) which is an intermediate inproducing 6-H quinolonecarboxylic acid derivatives having a strongantibacterial activity and which has a mother nucleus common to the 6-Hquinolonecarboxylic acid derivatives.

This invention also provides a compound represented by formula (V):

wherein R¹ represents a lower alkyl group and A represents nitrile groupor an alkoxycarbonyl group. This compound is an intermediate useful forsynthesizing the compound represented by formula (VI) which is anintermediate in producing 6-H quinolonecarboxylic acid derivativeshaving a strong antibacterial activity and which has a mother nucleuscommon to the 6-H quinolonecarboxylic acid derivatives.

This invention also provides a compound represented by formula (VI):

wherein R¹ represents a lower alkyl group. This compound is anintermediate useful for synthesizing the compound represented by formula(VI) which is an intermediate in producing 6-H quinolonecarboxylic acidderivatives having a strong antibacterial activity and which has amother nucleus common to the 6-H quinolonecarboxylic acid derivatives.

Effects of the Invention

The method according to the present invention is commercially quiteadvantageous since it reduces the number of production steps and doesnot involve low reaction temperature nor use of reagents which aredifficult to handle.

EMBODIMENTS TO CARRY OUT THE INVENTION

R¹ in formulae (I), (II) and (IV) to (VI) is preferably a straight orbranched lower alkyl group containing 1 to 3 carbon atoms such asmethyl, ethyl, n-propyl, or isopropyl. R¹ is most preferably methylgroup.

R² and R³ in formulae (II) and (III) is preferably a straight orbranched lower alkyl group containing 1 to 4 carbon atoms such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. R²and R³ are more preferably methyl group or ethyl group, and mostpreferably methyl group.

A in formulae (II) to (V) is preferably nitrile group or analkoxycarbonyl group containing 2 to 5 carbon atoms such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, or isobutoxycarbony. A is most preferablymethoxycarbonyl or ethoxycarbonyl.

X in formula (I) is preferably a halogen atom such as chlorine orbromine, an alkanoyloxy group containing 2 to 6 carbon atoms such asacetoxy group or propionyloxy group, a halogenated alkanoyloxy groupcontaining 2 to 6 carbon atoms such as trifluoroacetoxy group, or asubstituted or unsubstituted aroyloxy group containing 7 to 11 carbonatoms such as benzoyloxy group or 2-methyl-6-nitrobenzoyloxy group. X ismost preferably a halogen atom or 2-methyl-6-nitrobenzoyloxy group.

The compounds of formula (II) are novel compounds. Particularlypreferred compounds of formula (II) are those wherein R¹ is methylgroup; the group of the formula:

is dimethylamino group or diethylamino group; and A is nitrile group,methoxycarbonyl group, or ethoxycarbonyl group.

The compounds of formula (I) wherein X is an acyloxy group are novelcompounds. The acyloxy group is preferably an alkanoyloxy groupcontaining 2 to 6 carbon atoms, a halogenated alkanoyloxy groupcontaining 2 to 6 carbon atoms, or a substituted or unsubstitutedaroyloxy group containing 7 to 11 carbon atoms.

Next, reaction steps involved in the production of compound (VI)starting from the substituted benzoic acid is described in detail.Compound (VI) is an intermediate in the production of thequinolonecarboxylic acid antibacterial and contains a mother nucleuscommon to the quinolonecarboxylic acid antibacterial.

Substituted Benzoic Acid→Compound (I)

The substituted benzoyl halide compound of formula (I) (wherein X is ahalogen) is produced by reacting a substituted benzoic acid with ahalogenating agent such as thionyl chloride or oxalyl chloridepreferably at a stoichiometric ratio (molar ratio) of about 1:1.Exemplary solvents which may be used include ether compounds such astetrahydrofuran, diethyl ether, dioxane, and dimethoxyethane; aromaticcompounds such as benzene, toluene, and xylene; chlorinated compoundssuch as methylene chloride and chloroform; ester compounds such asmethyl acetate and ethyl acetate; and nitrile compounds such asacetonitrile. The reaction is conducted at a temperature in the range of0 to 170° C., preferably from room temperature to 110° C. Usually, thereaction proceeds smoothly at a temperature in the vicinity of roomtemperature. The reaction time which depends on the solvent and thereaction temperature chosen is generally in the range of 1 to 15 hours.

The substituted benzoyl anhydride of formula (I) is produced by reactinga substituted benzoic acid with an acid anhydride such as aceticanhydride, trifluoroacetic anhydride, or benzoic anhydride, preferablywith 2-methyl-6-nitrobenzoic anhydride, preferably at a stoichiometricratio (molar ratio) of about 1:1. The solvent used may be any of thesolvents used for producing substituted benzoyl halides, and ispreferably chlorinated compounds such as methylene chloride andchloroform. The reaction temperature is in the range of −20° C. to 100°C., preferably 20° C. to 80° C. The reaction time which depends on thesolvent and the reaction temperature chosen is generally in the range of2 to 10 hours.

Compound (I)→Compound (II)

The compound of formula (II) is produced by reacting the compound offormula (I) with the compound of formula (III) preferably at astoichiometric ratio (molar ratio) of about 1:1, and more specifically,by using 0.8 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents of abase in relation to the acid halide or acid anhydride (I). Exemplarybases which may be used include tertiary amines such as pyridine,triethylamine, N-methylpiperidine, and N,N-dimethylaminopyridine, anduse of triethylamine is preferred. Exemplary solvents which may be usedinclude ether compounds such as tetrahydrofuran, diethyl ether, dioxane,and dimethoxyethane; aromatic compounds such as benzene, toluene, andxylene; chlorinated compounds such as methylene chloride and chloroform;ester compounds such as methyl acetate and ethyl acetate; and nitrilecompounds such as acetonitrile. The reaction is accomplished at atemperature in the range of 0 to 170° C., preferably from roomtemperature to 110° C.

After completion of the reaction, the product is collected by filteringoff the salts precipitated as a result of the reaction and concentratingthe filtrate; or by adding the reaction mixture which has beenoptionally concentrated to water, removing the salts that are produced,and extracting the filtrate with a water-insoluble organic solvent. Thetarget product can be obtained in a high purity by removing the solventfrom the extract. However, when further purification is required, a pureproduct may be isolated by using column chromatography.

Compound (II)→Compound (IV)

Compound (IV) is produced by reacting compound (II) withfluorocyclopropylamine or its salt such as tosylate preferably in thepresence of a base such as triethylamine preferably at a stoichiometricratio (molar ratio) of about 1:1. The solvent which may be used in thisreaction is not particularly restricted as long as it does not interferewith the reaction, and exemplary solvents include ether compounds suchas diethyl ether, tetrahydrofuran, and dioxane; aliphatic compounds suchas hexane and cyclohexane; aromatic compounds such as benzene, toluene,and xylene; chlorinated compounds such as methylene chloride,chloroform, and carbon tetrachloride; and ester compounds such as methylacetate and ethyl acetate. The reaction temperature is in the range of−20 to 100° C., preferably 0 to 50° C. The reaction time variesdepending on the reaction temperature, and is from several minutes to 10hours, and usually 2 hours or less.

Compound (IV)→Compound (V)

Compound (V) is produced by treating compound (IV) with a base. Thesolvents which may be used in this reaction include ether compounds suchas diethyl ether, tetrahydrofuran, and dioxane; and aprotic polarsolvents such as N,N-dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide, sulfolane, and N-methylpyrrolidone, anduse of N,N-dimethylformamide is preferred. The base which may be usedincludes sodium hydride, butyllithium, sodium methoxide, potassiumt-butoxide, metallic sodium, sodium carbonate, potassium carbonate, andpotassium fluoride, and use of potassium carbonate is preferred. Thebase is used in an amount of 1 to 20 equivalents, preferably 1 to 5equivalents in relation to compound (IV). The reaction temperaturevaries depending on the base used and is typically in the range of fromroom temperature to 300° C., preferably from room temperature to 100° C.The reaction time varies depending on the reaction temperature and is inthe range of 1 to 48 hours, typically 6 to 24 hours.

Compound (V)→Compound (VI)

Compound (VI) may be produced by the hydrolysis of compound (V). In thisreaction, the hydrolysis may be conducted under either acidic oralkaline conditions as long as the quinolone skeleton is not decomposed.The acid used in the hydrolysis under acidic conditions includesinorganic acids such as hydrochloric acid, sulfuric acid and nitricacid, and carboxylic acids such as formic acid and acetic acid, and thereaction may be conducted at a temperature in the range of roomtemperature to 300° C., preferably room temperature to 100° C. The acidis preferably used in an amount of 1 to 50 equivalents, preferably 1 to10 equivalents in relation to compound (VI). The reaction time may varydepending on the reaction temperature, and is typically in the range of1 to 48 hours, usually 1 to 24 hours. The base used in the hydrolysisunder alkaline conditions includes inorganic bases such as sodiumhydroxide and potassium hydroxide, and the reaction may be conducted ata temperature in the range of from room temperature to 300° C.,preferably from room temperature to 100° C. The base is used in anamount of 1 to 50 equivalents, preferably 1 to 10 equivalents inrelation to compound (VI). The reaction time may vary depending on thereaction temperature, and is typically in the range of 1 to 48 hours,usually 1 to 24 hours.

The thus obtained compound (VI) may be reacted with a3-(R)-(1-aminocyclopropyl)pyrrolidine having its amino group protected,and then, the protective group of the amino group may be removed toproduce the quinolone carboxylic acid derivative represented by formula(A) which is useful as an antibacterial agent (see the followingreaction scheme). Exemplary groups which may be used for protecting theamino group include alkoxycarbonyl groups, aralkyloxycarbonyl groups,acyl groups, aralkyl groups, alkyl groups, and substituted silyl groups.The reaction may be conducted under the conditions specified inWO02/40478. For example, the reaction may be conducted in the presenceof abase such as triethylamine, and the reaction product may behydrolyzed by using hydrochloric acid or the like to thereby detach theprotective group. Compound (A) may also be isolated in the form of anacid addition salt or a hydrate thereof.

EXAMPLES

Next, the present invention is described in further detail by referringto the Examples and Reference Examples.

Example 1 Production of Ethyl3-dimethylamino-2-(2,4-difluoro-3-methoxybenzoyl)acrylate

To 10.0 g of 2,4-difluoro-3-methoxybenzoic acid was added 40 mL oftetrahydrofuran. To this solution was added 0.4 mL ofN,N-dimethylformamide, and then 8 mL of thionyl chloride was addeddropwise with stirring to this mixture at room temperature. Aftercompletion of the dropwise addition, Dimroth condenser was installed,and the mixture was heated under reflux for 2 hours. After allowing thereaction mixture to cool, the solvent was distilled away. The resultingacid chloride was dissolved in 40 mL of tetrahydrofuran, and 12 ml oftriethylamine was added to this solution and the mixture was stirred.After 30 minutes, 8.37 g of ethyl N,N-dimethylaminoacrylate was addeddropwise, and after completing the dropwise addition, the mixture washeated under reflux for 2 hours. After completion of the reaction, theprecipitated solid was removed by suction filtration, and the filtratewas concentrated under reduced pressure to obtain 23.3 g of the desiredtitle compound as a dark brown oily compound.

¹H-NMR (400 MHz, CDCl₃) 0.94 (t, J=6.8 Hz, 3H), 3.97 (s, 3H), 3.98 (q,J=6.8 Hz, 2H), 6.91 (t, J=8.8, Hz, 1H), 7.20-7.30 (m, 1H), 7.77 (s, 1H).

Example 2 Production of Ethyl(E,Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-[(1R,2S)-fluorocyclopropylamine]acrylate

To 22.3 g of ethyl3-dimethylamino-2-(2,4-difluoro-3-methoxybenzoyl)acrylate was added 110mL of ethyl acetate. While stirring the mixture at room temperature,20.4 g of (1R,2S)-2-fluorocyclopropylamine tosylate was added, and then1.5 g of triethylamine was added dropwise to the mixture. After 2 hours,30 mL of water was added to the reaction mixture, and the mixture wasextracted with 25 mL of ethyl acetate and dried with anhydrous sodiumsulfate. Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain 20.5 g of the titlecompound as a dark brown oily product.

Example 3 Production of Ethyl7-fluoro-1-[(1R,2S)-2-fluorocyclopropylamine]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

To 20.5 g of ethyl(E,Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-[(1R,2S)-fluoro-cyclopropylamine]acrylatewas added 40 mL of N,N-dimethylformamide, and the mixture was dissolvedat room temperature. To the solution was added 12.5 g of potassiumcarbonate in powder form, and after the addition, the mixture wasstirred at room temperature for 16.5 hours. After completion of thereaction, the reaction mixture was cooled in an ice bath, and 200 mL ofwater was gradually added dropwise. After completion of the dropwiseaddition, the precipitated crystals were filtered with suction. Theresulting crude crystals were washed as a slurry with 40 mL of water,filtered, and further washed as a slurry with 120 mL of isopropyl ether.The resulting yellowish brown crystals were transferred to a dish, andair-dried to obtain 12.5 g of the title compound.

¹H-NMR (270 MHz, CDCl₃) 1.41 (t, J=7.3 Hz, 3H), 1.52-1.65 (m, 2H),3.78-3.92 (m, 1H), 4.04 (d, J=2.0 Hz, 3H), 4.39 (q, J=7.3 Hz, 2H), 4.86(ddt, J=62.4, 3.5, 5.4 Hz, 1H), 7.21 (dd, J=9.1, 10.4 Hz, 1H), 8.24 (dd,J=5.9, 9.1 Hz, 1H), 8.57 (d, J=1.4 Hz, 1H).

Example 4 Production of7-fluoro-1-[(1R,2S)-2-fluorocyclopropylamine]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

2N aqueous solution of sodium hydroxide (180 mL) was added dropwise to32.4 g of the ethyl7-fluoro-1-[(1R,2S)-2-fluorocyclopropylamine]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylateat room temperature, and the mixture was stirred at 50° C. for 0.5 hour.After confirming disappearance of the starting materials, the reactionmixture was allowed to cool, 160 mL toluene was added dropwise thereto,and the mixture was stirred for 10 minutes. The solution was separatedand an aqueous layer was added dropwise to 180 mL of 3N hydrochloricacid cooled in an ice bath. The precipitated crystals were filtered withsuction, 160 mL of water was added thereto, and the resulting slurry wasstirred at room temperature. After 15 minutes, the slurry was filteredagain to obtain yellow crude crystals. To the thus obtained crudecrystals was added 320 mL of acetonitrile, and the mixture was heatedunder reflux to completely dissolve the crystals. The solution wascooled with stirring to an internal temperature of 0° C. to precipitatecrystals. The crystals were separated by filtration to obtain the titlecompound as whitish-yellow crystals (22.14 g).

¹H-NMR (270 MHz, CDCl₃) 1.55-1.73 (m, 2H), 4.01 (m, 1H), 4.10 (d, J=2.0Hz, 3H), 4.80-4.84 (md, J=62.7 Hz, 1H), 4.96-5.00 (md, J=62.7 Hz, 1H),7.35 (dd, J=9.0, 10.3 Hz, 1H), 8.27 (dd, J=5.9, 9.0 Hz, 1H), 8.85 (s,1H), 14.52 (br s, 1H).

Analysis of the pale white crystals

Calculated value for C₁₄H₁₁F₂NO₄: C, 56.95; H, 3.76; N, 4.74; F, 12.87.

Measured value: C, 56.80; H, 3.73; N, 4.76; F, 12.83.

Example 5 Production of Ethyl3-dimethylamino-2-(2,4-difluoro-3-methoxybenzoyl)acrylate (Mixed AcidAnhydride Method)

To 376 mg of the 2,4-difluoro-3-methoxybenzoic acid was added 40 mL oftetrahydrofuran. After adding 0.75 ml of triethylamine, 20 mg ofN,N-dimethylaminopyridine and 689 mg of 2-methyl-6-nitrobenzoicanhydride to this solution, the mixture was stirred at room temperature.After 2 hours, mixed acid anhydrides were confirmed by TLC, and 430 mgof ethyl N,N-dimethylaminoacrylate was added dropwise thereto. Aftercompletion of the dropwise addition, the mixture was stirred for 24hours. After completion of the reaction, water was added to the reactionmixture, and the separated solution was extracted with ethyl acetate anddried with anhydrous sodium sulfate. After removing the sodium sulfateby filtration, the filtrate was concentration under reduced pressure toobtain 511 mg of a dark brown oily product. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound.

1. A method for producing a compound represented by the followingformula (VI):

wherein R¹ represents a lower alkyl group which comprises the steps oftreating a compound represented by formula (IV):

wherein R¹ is as defined above and A represents nitrile group or analkoxycarbonyl group with potassium carbonate in DMF to produce acompound represented by formula (V):

wherein R¹ and A are as defined above, and hydrolyzing this compound. 2.The method according to claim 1, wherein the compound represented byformula (IV) is produced by reacting a compound represented by formula(II):

wherein R² and R³ are the same or different lower alkyl groups and R¹and A are as defined above with (1R,2S)-2-fluorocyclopropylamine.
 3. Themethod according to claim 2, wherein the compound represented by formula(II) is produced by reacting a compound represented by formula (I):

wherein R¹ is a lower alkyl group and X represents a halogen atom or anacyloxy group with a compound represented by formula (III):

wherein A, R² and R³ are as defined above.
 4. The method according toclaim 3, wherein the compound represented by formula (I) is produced byreacting a compound represented by formula:

wherein R¹ and X are as defined above with a halogenating agent or anacid anhydride.
 5. The method according to claim 1, wherein the group Ais a nitrile group.
 6. The method according to claim 2, wherein R² andR³ are methyl groups.
 7. The method according to claim 1, wherein R¹ isa methyl group.
 8. The method according to claim 3, wherein X is ahalogen atom or 2-methyl-6-nitrobenzoyl oxy group.
 9. The methodaccording to claim 4, wherein the compound of formula (I) is reactedwith 2-methyl-6-nitrobenzoic anhydride.
 10. The method according toclaim 4, wherein the compound of formula (I) is reacted with at leastone selected from the group consisting of acetic anhydride,trifluoroacetic anhydride and benzoic anhydride.
 11. The methodaccording to claim 4, wherein the compound of formula (I) is reactedwith a halogenating agent or an acid anhydride at about a 1:1stoichiometric ratio.
 12. The method according to claim 2, wherein thecompound of formula (II) is reacted with(1R,2S)-2-fluorocyclopropylamine in an acid form.
 13. The methodaccording to claim 1, wherein the hydrolyzing is carried out withoutdecomposing the quinoline skeleton of the compound of formula (V). 14.The method according to claim 1, further comprising: reacting thecompound of formula (VI) with a compound of formula


15. The method according to claim 1, wherein the compound represented byformula (IV) is treated with potassium carbonate in DMF at a temperatureof from room temperature to 100° C. for a period of from 1 to 24 hours.16. The method according to claim 1, wherein the compound of formula(IV) is treated with five equivalents of potassium carbonates inrelation to the compound of formula (IV).